Maternal Serum Interleukin-6, C-Reactive Protein, and Matrix Metalloproteinase-9 Concentrations as Risk Factors for Preterm Birth <32 Weeks and Adverse Neonatal Outcomes

ABSTRACT

Elevated concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) in fetal and neonatal compartments have been associated with an increased risk for preterm birth (PTB) and/or neonatal morbidity. The purpose of this study was to determine if the maternal serum concentration of IL-6, CRP, and MMP-9 in women at risk for PTB, who are not in labor and have intact membranes, are associated with an increased risk for PTB <32 weeks and/or neonatal morbidity. Maternal serum samples collected from 475 patients enrolled in a multicenter randomized controlled trial of single versus weekly corticosteroids for women at increased risk for preterm delivery were assayed. Serum was collected at randomization (24 to 32 weeks' gestation). Maternal serum concentrations of IL-6, CRP, and MMP-9 were subsequently determined using enzyme-linked immunoassays. Multivariate logistic regression analysis was performed to explore the relationship between maternal serum concentrations of IL-6, CRP, and MMP-9 and PTB <32 weeks, respiratory distress syndrome (RDS), chronic lung disease (CLD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and any sepsis. Maternal serum concentrations of IL-6 and CRP, but not MMP-9, above the 90th percentile at the time of randomization were associated with PTB <32 weeks. In contrast, there was no significant relationship between RDS and NEC and the maternal serum concentration of IL-6, CRP, or MMP-9 (univariate analysis). The development of CLD was associated with a high (above 90th percentile) IL-6 and CRP in maternal serum, even after adjustment for gestational age (GA) at randomization and treatment group. However, when GA at delivery was added to the model, this finding was nonsignificant. Neonatal sepsis was more frequent in neonates born to mothers with a high maternal serum concentration of CRP (>90th percentile). However, there was no significant association after adjustment for GA at randomization and treatment group. Logistic regression analysis for each analyte indicated that high maternal serum concentrations of IL-6 and CRP, but not MMP-9, were associated with an increased risk of IVH (odds ratio [OR] 4.60, 95% confidence interval [CI] 1.86 to 10.68; OR 4.07, 95% CI 1.63 to 9.50) after adjusting for GA at randomization and treatment group. Most babies (25/30) had grade I IVH. When GA at delivery was included, elevated IL-6 remained significantly associated with IVH (OR 2.77, 95% CI 1.02 to 7.09). An elevated maternal serum concentration of IL-6 and CRP are risk factors for PTB <32 weeks and subsequent development of neonatal IVH. An elevated maternal serum IL-6 appears to confer additional risk for IVH even after adjusting for GA at delivery.

KEYWORDS

Maternal serum - cytokines - preterm birth - neonatal morbidity

REFERENCES

• 1 Goldenberg R L, Culhane J F, Iams J D, Romero R. Epidemiology and causes of preterm birth.  Lancet. 2008;  371 75-84
• 2 Romero R, Gomez R, Ghezzi F et al.. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition.  Am J Obstet Gynecol. 1998;  179 186-193
• 3 Goldenberg R L, Hauth J C, Andrews W W. Intrauterine infection and preterm delivery.  N Engl J Med. 2000;  342 1500-1507
• 4 Yoon B H, Jun J K, Romero R et al.. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy.  Am J Obstet Gynecol. 1997;  177 19-26
• 5 Yoon B H, Romero R, Park J S et al.. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years.  Am J Obstet Gynecol. 2000;  182 675-681
• 6 Romero R, Espinoza J, Kusanovic J P et al.. The preterm parturition syndrome.  BJOG. 2006;  113(Suppl 3) 17-42
• 7 Romero R, Yoon B H, Mazor M et al.. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes.  Am J Obstet Gynecol. 1993;  169 839-851
• 8 Goepfert A R, Goldenberg R L, Andrews W W National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network et al. The Preterm Prediction Study: association between cervical interleukin 6 concentration and spontaneous preterm birth.  Am J Obstet Gynecol. 2001;  184 483-488
• 9 Yoon B H, Romero R, Kim C J et al.. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity.  Am J Obstet Gynecol. 1995;  172 960-970
• 10 Yoon B H, Yang S H, Jun J K, Park K H, Kim C J, Romero R. Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count.  Obstet Gynecol. 1996a;  87 231-237
• 11 Yoon B H, Jun J K, Park K H, Syn H C, Gomez R, Romero R. Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes.  Obstet Gynecol. 1996b;  88 1034-1040
• 12 Martinez E, Figueroa R, Garry D et al.. Elevated amniotic fluid interleukin-6 as a predictor of neonatal periventricular leukomalacia and intraventricular hemorrhage.  J Matern Fetal Investig. 1998;  8 101-107
• 13 Weeks J W, Reynolds L, Taylor D, Lewis J, Wan T, Gall S A. Umbilical cord blood interleukin-6 levels and neonatal morbidity.  Obstet Gynecol. 1997;  90 815-818
• 14 Goepfert A R, Andrews W W, Carlo W et al.. Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity.  Am J Obstet Gynecol. 2004;  191 1375-1381
• 15 Yoon B H, Romero R, Yang S H et al.. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia.  Am J Obstet Gynecol. 1996;  174 1433-1440
• 16 Kassal R, Anwar M, Kashlan F, Smulian J, Hiatt M, Hegyi T. Umbilical vein interleukin-6 levels in very low birth weight infants developing intraventricular hemorrhage.  Brain Dev. 2005;  27 483-487
• 17 Yoon B H, Romero R, Park J S et al.. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis.  Am J Obstet Gynecol. 2000;  183 1124-1129
• 18 Yoon B H, Romero R, Kim K S et al.. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia.  Am J Obstet Gynecol. 1999;  181 773-779
• 19 Heep A, Behrendt D, Nitsch P, Fimmers R, Bartmann P, Dembinski J. Increased serum levels of interleukin 6 are associated with severe intraventricular haemorrhage in extremely premature infants.  Arch Dis Child Fetal Neonatal Ed. 2003;  88 F501-F504
• 20 Ghezzi F, Franchi M, Raio L et al.. Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery.  Am J Obstet Gynecol. 2002;  186 268-273
• 21 Yoon B H, Romero R, Shim J Y, Shim S S, Kim C J, Jun J K. C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis.  J Matern Fetal Neonatal Med. 2003;  14 85-90
• 22 Athayde N, Edwin S S, Romero R et al.. A role for matrix metalloproteinase-9 in spontaneous rupture of the fetal membranes.  Am J Obstet Gynecol. 1998;  179 1248-1253
• 23 Maymon E, Romero R, Pacora P et al.. Evidence of in vivo differential bioavailability of the active forms of matrix metalloproteinases 9 and 2 in parturition, spontaneous rupture of membranes, and intra-amniotic infection.  Am J Obstet Gynecol. 2000;  183 887-894
• 24 Romero R, Chaiworapongsa T, Espinoza J et al.. Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membranes.  Am J Obstet Gynecol. 2002;  187 1125-1130
• 25 Schulz C G, Sawicki G, Lemke R P, Roeten B M, Schulz R, Cheung P Y. MMP-2 and MMP-9 and their tissue inhibitors in the plasma of preterm and term neonates.  Pediatr Res. 2004;  55 794-801
• 26 Sweet D G, Curley A E, Chesshyre E et al.. The role of matrix metalloproteinases-9 and -2 in development of neonatal chronic lung disease.  Acta Paediatr. 2004;  93 791-796
• 27 Wapner R J, Sorokin Y, Thom E A National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network et al. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.  Am J Obstet Gynecol. 2006;  195 633-642
• 28 Papile L A, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.  J Pediatr. 1978;  92 529-534
• 29 Murtha A P, Greig P C, Jimmerson C E, Herbert W NP. Maternal serum interleukin-6 concentration as a marker for impending preterm delivery.  Obstet Gynecol. 1998;  91 161-164
• 30 Pfeiffer K A, Reinsberg J, Rahmun A, Schmolling J, Krebs D. Clinical application of maternal serum cytokine determination in premature rupture of membranes—interleukin-6, an early predictor of neonatal infection?.  Acta Obstet Gynecol Scand. 1999;  78 774-778
• 31 Turhan N O, Karabulut A, Adam B. Maternal serum interleukin 6 levels in preterm labor: prediction of admission-to-delivery interval.  J Perinat Med. 2000;  28 133-139
• 32 Lewis D F, Barrilleaux P S, Wang Y, Adair C D, Baier J, Kruger T. Detection of interleukin-6 in maternal plasma predicts neonatal and infectious complications in preterm premature rupture of membranes.  Am J Perinatol. 2001;  18 387-391
• 33 Goldenberg R L, Iams J D, Mercer B M Maternal-Fetal Medicine Units Network et al. The Preterm Prediction Study: toward a multiple-marker test for spontaneous preterm birth.  Am J Obstet Gynecol. 2001;  185 643-651
• 34 Bahar A M, Ghalib H W, Moosa R A, Zaki Z M, Thomas C, Nabri O A. Maternal serum interleukin-6, interleukin-8, tumor necrosis factor-alpha and interferon-gamma in preterm labor.  Acta Obstet Gynecol Scand. 2003;  82 543-549
• 35 Sozmen S, Mungan T, Micozkadioglu S D, Tapisiz O L, Tapisiz O L. Predictive value of maternal serum and vaginal interleukin-6 levels in preterm labor.  J Soc Gynecol Investig. 2005;  12 e1-e6
• 36 Pitiphat W, Gillman M W, Joshipura K J, Williams P L, Douglass C W, Rich-Edwards J W. Plasma C-reactive protein in early pregnancy and preterm delivery.  Am J Epidemiol. 2005;  162 1108-1113
• 37 Skrablin S, Lovric H, Banovic V, Kralik S, Dijakovic A, Kalafatic D. Maternal plasma interleukin-6, interleukin-1beta and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery.  J Matern Fetal Neonatal Med. 2007;  20 335-341
• 38 Trochez-Martinez R D, Smith P, Lamont R F. Use of C-reactive protein as a predictor of chorioamnionitis in preterm prelabour rupture of membranes: a systematic review.  BJOG. 2007;  114 796-801
• 39 Vogel I, Goepfert A R, Thorsen P et al.. Early second-trimester inflammatory markers and short cervical length and the risk of recurrent preterm birth.  J Reprod Immunol. 2007;  75 133-140